The recent FDA approval of ipilimumab (Yervoy(R), anti-CTLA4 antibody) for the treatment of metastatic melanoma and its introduction to clinical practice, have brought to the forefront a long recognized dilemma of cancer immunotherapy: is clinically detectable tumor enlargement the result of tumor infiltration by immune cells (tumor inflammation; good outcome) or an increased number of cancer cells (tumor progression; bad outcome). This is particularly relevant today as ipilimumab (IPI) is in daily clinical practice wit 50% of treated patients with metastatic melanoma facing tumor enlargement within 12 weeks of initiation of treatment. Albeit consensus recommendations do exist to allow for continuation of IPI therapy in the face of limited tumor progression (immune response RECIST criteria), oncologists in clinical practice are left with their best clinical judgment in differentiating tumo inflammation vs. tumor progression. Presently, there are no clinical tools to make this distinction and guide therapy decisions in this unique clinical setting of cancer immunotherapeutics. Over the past decade, work by Dr. Signore et al has resulted in the development of methodology for non-invasive detection of T lymphocyte organ infiltration using interleukin-2 (IL2) based scintigraphy. The group's most recent radiopharmaceutical (99mTc-HYNIC-IL2) builds upon prior IL2 labeling efforts (123I-IL2 and 99mTc-N2S-IL2) using a simplified labeling procedure with excellent detection of activated T lymphocytes in human tissues, including melanoma of the skin. We hypothesize that99mTc-HYNIC-IL2 scintigraphy will allow clinical differentiation of tumor inflammation vs tumor progression in patients undergoing IPI therapy for metastatic melanoma. We seek funding in support of a pilot clinical trial addressing: (1) feasibility/safety of 99mTc-HYNIC-IL2 scintigraphy in patients with metastatic melanoma undergoing IPI therapy; (2) correlation of tumor infiltrating lymphocyte (TIL) invasion assessed by 99mTc-HYNIC-IL2 scintigraphy vs. histology (total and subsets of TIL), as well as screen for peripheral blood correlates; and (3) correlation of TIL invasion (scintigraphy/histology) with tumor diameter (RECIST) and association with 2 year survival. Successful completion of this study will generate necessary preliminary data regarding the utility of 99mTc-HYNIC-IL2 scintigraphy as a guide for IPI therapy in advanced melanoma. We anticipate that 99mTc- HYNIC-IL2 scintigraphy will be able to non-invasively discriminate between tumor progression (low 99mTc- HYNIC-IL2 uptake) vs. tumor inflammation (high99mTc-HYNIC-IL2 uptake) on CT images of tumor masses. The current study will provide necessary data for a future, adequately powered study aimed at establishing the ability of 99mTc-HYNIC-IL2 scintigraphy to predict good clinical outcomes (survival at 2 years) in patients with metastatic melanoma undergoing standard-of-care IPI therapy PUBLIC HEALTH RELEVANCE: The introduction of ipilimumab into clinical practice of metastatic melanoma has brought to the forefront the issue of discriminating tumor enlargement as a result of tumor inflammation (infiltration by immune cells leading to good outcomes) versus tumor progression (further tumor proliferation leading to poor outcomes). In this study we seek to test the possibility that a radiolabeled interleukin-2 scintigraphic radiopharmaceutical (99mTc-HYNIC-IL2), known to detect organ infiltrating T cells in human autoimmune diseases, will also be able to detect tumor infiltrating T lymphocytes in metastatic melanoma patients undergoing ipilimumab therapy and discriminate tumor inflammation from tumor progression.